Despite recent advances in treatment, colorectal cancer is the third leading cause of cancer mortality in the US, and survival for advanced disease remains extremely low. The long-term objectives of this project are to investigate the clinical activity and biologic effects of oral Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKI) in colorectal cancer, and to develop a specific expertise in validated, quantitative pharmacodynamic assays to aid in the clinical development of cell signaling inhibitors. Although combination trials using EGFR inhibitors and chemotherapy were negative in other cancer types, EGFR is validated target in colorectal cancer, and a phase II trial combining gefitinib with FOLFOX has shown an impressive 80% response rate. EGFR mutations seen in other tumor types such as lung cancer have not been seen in colorectal cancer. This class of agents is clearly active in this disease, but optimal patient selection, the exact effects on colorectal tumors, and predictors of response are all significant unknowns. This application is structured around two IRB-approved protocols. Specific Aim #1 is a phase I study combining the oral EGFR TKI erlotinib with FOLFOX/bevacizumab in the advanced disease setting. The candidate is the principal investigator of the trial, and developed and coordinated biologic studies which include quantitative analysis of EGFR signaling in pre- and post-treatment biopsies in a subset of patients. Specific Aim #2 is a phase II trial written entirely by candidate (co-Principal Investigator) adding gefitinib to neoadjuvant 5-FU based chemoradiation for resectable rectal cancer. All subjects will have pre- and post-treatment tumor and normal colon biopsies to evaluate the biologic effects of the drugs. In both studies, biopsies occur after a "lead-in" period of monotherapy with the EGFR inhibitors to dissect their effects without other treatment. The central theme of both trials is to rationally incorporate EGFR inhibitors into the treatment of colorectal cancer as well as to increase our understanding of EGFR inhibitor pharmacological actions.